Polyglutamine length-dependent toxicity from α1ACT in Drosophila models of spinocerebellar ataxia type 6
ABSTRACTSpinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disease that results from abnormal expansion of a polyglutamine (polyQ) repeat. SCA6 is caused by CAG triplet repeat expansion in the gene CACNA1A, resulting in a polyQ tract of 19-33 in patients. CACNA1A, a bicistronic gene, encodes the α1A calcium channel subunit and the transcription factor, α1ACT. PolyQ expansion in α1ACT causes degeneration in mice. We recently described the first Drosophila models of SCA6 that express α1ACT with a normal (11Q) or hyper-expanded (70Q) polyQ. Here, we report additional α1ACT transgenic flies, which express full-length α1ACT with a 33Q repeat. We show that α1ACT33Q is toxic in Drosophila, but less so than the 70Q version. When expressed everywhere, α1ACT33Q-expressing adults die earlier than flies expressing the normal allele. α1ACT33Q causes retinal degeneration and leads to aggregated species in an age-dependent manner, but at a slower pace than the 70Q counterpart. According to western blots, α1ACT33Q localizes less readily in the nucleus than α1ACT70Q, providing clues into the importance of polyQ tract length on α1ACT localization and its site of toxicity. We expect that these new lines will be highly valuable for future work on SCA6.
[…] All fluorescence images were taken with an Olympus BX53 microscope and CellSens software (Olympus, Waltham, MA, USA). The same objective (10×) and camera settings (ISO 200, 500 ms capture time for each sample) were used for all images. Image capture and quantification (ImageJ, NIH) were conducted by separate investigators. Control and experimental flies were all imaged on the same day. ImageJ's freehand tool was used to outline and to quantify fluorescence readings from each fly eye. […]
Drosophila melanogaster, Homo sapiens, Mus musculus
Retinal Degeneration, Neurodegenerative Diseases, Spinocerebellar Ataxias, Drug-Related Side Effects and Adverse Reactions
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